Most nervous systems delegate the task of detecting and correcting sleep deficits to a minority of specialised cells. Like circuit breakers, these neurons keep a watch on a sleep-relevant aspect of their own physiology and trip the rest of the brain into sleep before a widespread overload occurs. Discovering what variable sleep-control cells are monitoring could be the smoking gun in understanding the function of sleep.
Writing in Nature, Olof Rorsman, Gero Miesenböck and colleagues report that sleep-inducing neurons in the brains of fruit flies respond to breakdown products of peroxidised membrane lipids. The neurons contain machinery that increases their electrical discharge when lipid-derived carbonyls accumulate. The centrepiece of this machinery is the ancillary β-subunit of a voltage-gated potassium channel, which flips back and forth between two states, forming a digital memory that can hold a single bit of information. The memory stores brief exposures to lipid peroxidation products by switching from one state (bit ‘0’) to the other (bit ‘1’) and is reset by membrane depolarization.
The authors suggest that sleep-control neurons use this mechanism to encode their recent lipid peroxidation history in the collective binary states of their potassium channel β-subunits. During waking, electrons leak from the respiratory chains of the inner mitochondrial membrane, producing superoxide and other reactive oxygen species (ROS), which attack the polyunsaturated fatty acyl chains of membrane lipids. The β-subunit population keeps a tally of the resulting membrane damage. This biochemical memory (which the authors equate to the accumulated sleep pressure) is read out and erased during subsequent sleep-promoting electrical activity, with the firing rate determined by the fraction of channels that have previously been set to bit ‘1’.
In an incisive demonstration of how lipid peroxidation dictates the need for sleep, the authors examined mutant flies that cannot rid their brains of lipid-derived carbonyls. They found that the animals were almost always asleep. 'The poor mutants literally sleep away their lives”, says Rorsman, “because their lipid peroxidation memories are always full.'
The work was funded by the European Research Council, the MRC, and Wellcome and involved a collaboration with chemists Max Müller and Bernhard Spengler at Justus-Liebig-Universität Giessen.
Read the paper here